Epidemiological studies have shown that the epsilon4 allele of apolipoprotein E (apoE) is associated with an increased risk for Alzheimer's disease (AD) while the epsilon2 allele is associated with a decreased risk. ApoE has 3 common isoforms in humans, E2, E3, and E4. Genetic, biochemical, and animal studies strongly suggest that apoE is likely to influence AD pathogenesis via effects on the metabolism of the 38-43 amino acid amyloid-beta (Abeta) peptide. By crossing amyloid precursor protein (APP) transgenic mice that develop AD-like pathology with Apoe- /- mice and transgenic mice that express human apoE isoforms, we have found that the presence of apoE is critical in the process by which Abetaa converts from soluble to fibrillar forms (amyloid) with neuritic plaque formation and cerebral amyloid angiopathy (CAA). The expression of human apoE (as compared to murine apoE or no apoE) markedly delays Abeta deposition suggesting that apoE also plays an important role in Abeta clearance. New data suggest that the LDL receptor (LDLR) should be re-explored as a potential modulator of apoE/Abeta clearance in vivo. Determining the effects of altering the levels of different apoE isoforms on Abeta in vivo as well as the mechanism(s) underlying these effects is likely to lead to important insights into AD and CAA pathogenesis and treatment. Thus, we hypothesize that the level and composition of human apoE isoforms will alter both the time course and amount of Abeta deposition in an isoform-specific fashion via effects on Abeta clearance and that human apoE isoforms play a role in CNS Abeta clearance in part via LDLR. These hypotheses will be tested in the following aims: Aim 1: To determine if the level of expression of the human apoE isoforms (via different techniques) influences Abeta-related pathology in APP transgenic mice. Aim 2: To assess the mechanism(s) by which apoE influences CNS Abeta metabolism in vivo we will use a novel CNS to blood Abeta efflux assay and a new brain Abeta microdialysis technique. Aim 3: To investigate the role of the apoE receptor, LDLR, in Abeta metabolism and related pathology in vitro and in APP transgenic mice. Aim 4: To determine the role of the cholesterol efflux pump, ABCA 1, in modulating the levels and metabolism of apoE, cholesterol, phospholipid, and Abeta in the brain.